With only days left before Inovio Pharmaceuticals Inc. planned to initiate a phase II/III trial of its COVID-19 DNA vaccine candidate, INO-4800, and its accompanying delivery device, the FDA placed a partial clinical hold on the company’s study.

This is the study’s second delay as the company originally planned to begin in July or August. November is now the earliest potential start date.

Inovio told BioWorld that the company and its partners are continuing to prepare for the phase II/III trial “following resolution of the FDA’s partial clinical hold.”

The small biotech said it plans to respond to the FDA’s questions in October and then await the agency’s response, which is due within the following 30 days. The action does not impinge upon the ongoing phase I study of the COVID-19 spike glycoprotein modulator and is not due to any adverse events in the study, the company said. None of the company’s other candidates in development are affected by the partial hold either, Inovio added.

J. Joseph Kim, president, CEO and director, Inovio

In the meantime, the Plymouth Meeting, Pa.-based company’s stock (NASDAQ:INO) struggled Sept. 28 as shares traded 28.34% lower to close at $12.14. The shares are still priced more highly than they were on Sept. 30, 2019, when they went for $2.05. They peaked in the past 12 months at $31.69 per share on June 29.

The delivery device set for the planned phase II/III, the Cellectra 2000, is designed to work by reversibly opening small pores in the skin by using a brief electrical pulse so that the treatment can be administered.

“For our part, today’s disclosure brings about more questions than answers as it’s unclear if the delay stems from specific questions around the Cellectra 2000 delivery device, trial design (INO had indicated running a trial in just 2k high-risk patients), or both,” Piper Sandler analysts wrote Sept. 28.

On June 23, Inovio said it received $71 million in funding from the U.S. Department of Defense to support the procurement of Cellectra 2000 devices and the large-scale manufacture of the Cellectra 3PSP smart device. That came after the company received a $5 million grant in March from the Bill and Melinda Gates Foundation to accelerate the testing and scale-up of Cellectra.

The Cellectra 3PSP leverages aspects of the Cellectra 2000, which is an earlier version of the 3PSP. The Cellectra 3PSP is a small, portable, battery-powered intradermal device intended for use in administering the company’s vaccines and therapies. It operates on AA batteries and can be stockpiled in large quantities without special maintenance. The company said it plans to produce initial supplies of Cellectra 3PSP at its San Diego plant and show how design and scale-up of the manufacturing process should be done, setting the stage for contract manufacturers to step in and help shoulder the load if necessary.

Development of the device began last summer with $8.1 million in funding from the U.S. Defense Threat Reduction Agency’s Medical CBRN Defense Consortium. The award was also earmarked for the evaluation of DNA vaccines developed by the U.S. Army Medical Research Institute of Infectious Diseases using the Cellectra 3PSP device.

In August, Inovio said INO-4800 was effective in protecting nonhuman primates (NHPs, specifically rhesus macaques) from live virus challenge 13 weeks after the last vaccination. The protective results were mediated by memory T- and B-cell immune responses from INO-4800 vaccination, Inovio said. The results, submitted to a peer-reviewed journal and published on the non-peer-reviewed online preprint site Biorxiv, demonstrate that INO-4800 reduced viral load in both the lower lungs and nasal passages in NHPs that received two doses of INO-4800 (1 mg) four weeks apart and then were challenged with live virus 13 weeks after the second dose (study week 17).

In June, an analyses of 1-mg and 2-mg dose cohorts after two doses at week six in the company’s phase I study of INO-4800 in treating COVID-19 infection showed 94% (34 of 36) demonstrated overall immunological response rates based on preliminary data assessing humoral and T-cell immune responses. One participant in the 1-mg cohort and two in the 2-mg cohort were excluded from the analyses as they tested positive for COVID-19 immune responses at study entry, indicating prior infection.

On Sept. 8, Inovio said Thermo Fisher Scientific signed a letter of intent to manufacture INO-4800. Thermo Fisher joins other CDMOs in the company’s manufacturing consortium, aimed at scaling commercial production of the vaccine. Inovio plans to have 100 million doses manufactured in 2021, subject to FDA approval for use in COVID-19. At peak capacity, Thermo Fisher projects that it could produce at least 100 million doses of INO-4800 annually.

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